title: Inhibition of cytochrome p450 enzymes by the e- and z-isomers of norendoxifen.
abstract: Aromatase catalyzes the conversion of testosterone to estradiol and is the main source of endogenous estrogen in postmenopausal women. Aromatase inhibitors (AIs) are used to treat postmenopausal women with hormone receptor-positive breast cancer. Norendoxifen [4-(1-(4-(2-aminoethoxy)phenyl)-2-phenylbut-1-en-1-yl)phenol], an active metabolite of the selective estrogen receptor modulator tamoxifen, has been shown to be a potent competitive AI, with an IC50 of 90 nM. To obtain data relevant to the clinical use of norendoxifen, the primary objective of this study was to investigate norendoxifen's inhibitory capability on enzymes related to drug-drug interactions. We determined the inhibitory ability of norendoxifen against important drug-metabolizing cytochrome P450 enzymes, including CYP1A2, CYP2A6, CYP3A4, CYP3A5, and CYP2C19, to establish the potency of norendoxifen as a potential cause of drug-drug interactions. A second objective was to determine the effects of E- and Z-norendoxifen on the inhibition of these enzymes to further characterize the isomers' selectivity. The inhibitory abilities of E-, mixed, and Z-norendoxifen against recombinant aromatase (CYP19), CYP1A2, CYP3A4, CYP3A5, and CYP2C19 were tested using microsomal incubations. Mixed norendoxifen inhibited these enzymes with Ki values of 70 ± 9, 76 ± 3, 375 ± 6, 829 ± 62, and 0.56 ± 0.02 nM, respectively. E-Norendoxifen had a 9.3-fold-higher inhibitory ability than Z-norendoxifen against CYP19, while E- and Z-norendoxifen had similar potencies against CYP1A2, CYP3A4, CYP3A5, and CYP2C19. These results suggest that norendoxifen is able to act as a potent AI, and that its E-isomer is 9.3-fold more potent than the Z-isomer.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indiana Institute for Personalized Medicine, Indianapolis, Indiana 46202, USA. jinzliu@iu.edu
authors.forename: Jinzhong
authors.initials: J
authors.lastname: Liu
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Flockhart
authors.forename: Deshun
authors.initials: D
authors.lastname: Lu
authors.forename: Wei
authors.initials: W
authors.lastname: Lv
authors.forename: Wenjie Jessie
authors.initials: WJ
authors.lastname: Lu
authors.forename: Xu
authors.initials: X
authors.lastname: Han
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
mesh_terms: D047072:Aromatase Inhibitors / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D013237:Stereoisomerism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D047072:Aromatase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; C574385:N,N-didesmethyl-4-hydroxytamoxifen; D013629:Tamoxifen; D003577:Cytochrome P-450 Enzyme System